A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library. These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex.

中文翻译：

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SAR和2-（喹啉-4-基氧基）乙酰胺作为结核分枝杆菌细胞色素bc1抑制剂的鉴定。

GSK先前进行的表型筛选确定了2-（quinolin-4-yloxy）乙酰胺是结核分枝杆菌（Mtb）的有效生长抑制剂。我们报告了化合物类别的初步结构-活性关系（SAR）研究的结果，该化合物产生了更有效的抑制剂。发现Mtb细胞色素bd氧化酶缺失突变体（cydKO）对化合物库的大多数成员高度敏感，而带有qcrB基因单核苷酸多态性的菌株，该基因编码甲萘醌细胞色素c氧化还原酶（bc1）复合物的亚基，对图书馆有抵抗力。这些结果表明，Mtb生长抑制剂的2-（quinolin-4-yloxy）乙酰胺类可以添加到越来越多的针对结核分枝杆菌bc1复合体的支架中。